DESCRIPTION: (Applicant's Abstract) The proposed research will determine how pre-treatment with nicotine or the nicotinic antagonist mecamylamine modifies the subsequent responses to cigarette smoking. Subjective, cardiovascular, and hormonal indices as well as cognitive performance will be measured before and after different doses of nicotine are presented in cigarette smoke. In Study 1, tolerance induced by pre-exposure to nicotine (with nicotine skin patches) will be assessed by measuring the subsequent responses to controlled doses of nicotine delivered in cigarette smoke. In Study 2, tolerance to nicotine induced by cigarette smoking will be compared to tolerance resulting from transdermal nicotine administration. A follow-up study (Study 3) will seek to relate individual differences in daily smoking patterns to differences in the susceptibility to tolerance produced by nicotine. Study 4 will examine blockade of the various responses to cigarette smoke after oral administration of mecamylamine. Because administration of nicotine and mecamylamine each attenuate subsequent responses to cigarette smoking, Study 5 will characterize the effects of combined nicotine/mecamylamine administration, which has shown considerable promise in smoking cessation treatment. Ad lib smoking behavior and responses to controlled doses of cigarette smoke will be measured during a two week period, to assess the extent to which nicotine and mecamylamine, administered separately or in combination, reduce the rewarding actions of inhaled nicotine and promote extinction of cigarette smoking behavior. Subsequently, participants will quit smoking using nicotine replacement and abstinence will be correlated with the degree to which different effects of cigarette smoking were attenuated by nicotine or mecamylamine treatment. The results of these studies will contribute to the understanding of factors mediating the reinforcing actions of nicotine that underlie tobacco dependence, and shed light on the mechanisms of action of effective smoking cessation treatments.